The two chemical carcinogens, 7,12-dimethylbenz(a)anthracene and aflatoxin B1, must undergo metabolic conversion by an NADPH-requiring mixed function oxidase to their ultimate cytotoxic and carcinogenic forms. Both of these carcinogens are structurally similar to steroids. We have found that estradiol-17 beta protects cultured rodent cells against 7,12-dimethylbenz(a)anthracene and aflatoxin-induced cytotoxicity and malignant transformation, while related steroid hormones show significantly less protective effect. Since estradiol-17 beta has been shown by others to be a competitive inhibitor of the mixed function oxidase, it may protect by inhibiting the formation of the reactive cytotoxic and carcinogenic metabolites. Our observed protective effect of estrogen is consistant with certain clinical studies in women, which indicate a much reduced incidence of cancer in women on prolonged estrogen therapy. We have also found that the adrenal steroid, dehydroepiandrosterone, protects against carcinogen-induced toxicity and transformation in cultured cells. Subnormal plasma concentrations of this steroid have been observed in women with benign and malignant breast tumors. Dehydroepiandrosterone has been reported by a number of investigators to be a potent inhibitor of glucose-6-phosphate dehydrogenase, which is the primary source of extra-mitochondrial NADPH. Since NADPH is a necessary co-factor for the activity of the mixed function oxidase, dehydroepiandrosterone may protect by reducing NADPH formation.